APOLIPOPROTEIN E (apoE) and the β-amyloid peptide are both found in the senile plaques associated with Alzheimer's disease. Several studies have recently determined that apoE can prevent β-amyloid fibril (Aβf) formation in vitro. In vivo, apoE is normally associated with a lipid source. We show that both recombinant and purified plasma apoE inhibit Aβf formation in a dose-dependent manner. The three major apoE isoforms were equipotent at inhibiting Aβf formation. ApoE associated with either cholesterol-containing liposomes or very low density lipoproteins displayed less potent inhibition of Aβf formation than their unlipidated counterparts. These results indicate that the presence of associated lipids reduce the ability of apoE to inhibit the formation of Aβf in vitro.